Biologically, angiotensinogen is converted via renin to angiotensin I, which is subsequently converted to angiotensin II (AngII) by converting enzymes such as angiotensin converting enzyme (ACE) and the like in vivo, resulting AngII has a potent and pleiotropic physiological action.
As receptors for AngII, the angiotensin type 1 receptor (hereinafter to be indicated as AT1 receptor) and AT2 receptor have been identified. It has been generally understood that conventionally well-known actions of AngII such as pressor effect on blood pressure, vasoconstriction and other effects are mainly mediated by classical AT1 receptors. On the other hand, the physiological roles of AT2 receptor have been rapidly revealed in recent years. The action via AT2 receptor mostly opposes the effect mediated by AT1 receptor in a number of cells and tissues and AT2 receptor mainly acts toward the prevention of diseases progression in the course of the onset and the development, as evidenced by its antiproliferative, antihypertrophic and antihypertensive effects, promotion of apoptosis, inhibition of extracellular matrix production and the like. While AT2 receptor is highly expressed in a wide range in fetal life, the expression level rapidly decreases after birth. However, it has become known that tissue-specific re-expression of AT2 under pathological conditions, such as vascular injury, cardiovascular remodeling after myocardial infarction and the like, thereby the significance of AT2 receptor involved in the prevention of the onset and progress of various diseases is much attracting attention.
Predicted pharmacological actions generally via AT2 receptor activation have been reported in several papers including a paper from de Gasparo et al. (see non-patent reference 1). Thus, a variety of therapeutic or preventive effects in several diseases could be expected as pharmaceutical use of AT2 receptor agonist. As its target diseases, various groups of disorders involving the renin-angiotensin-aldosterone system (hereinafter to be indicated as RAAS), such as metabolic diseases, cardiovascular diseases and the like are considered, and stroke, renal disease, cardiac disease, hypertension, diabetes, metabolic syndrome and the like can be given as examples.
As nonpeptidic AT2 receptor agonist, 3-phenyl-2-thiophene sulfonamide or biphenyl sulfonamide compounds have heretofore been disclosed (see non-patent references 2, 3, patent references 1, 2, 3, 4, 5, 6, 7, 8, 9). However, the compounds described in these non-patent references and patent references are all characterized by a combination of a bisaryl structure and a sulfonamide group and the like, and a sulfonyl malonamide derivative is not clearly indicated or suggested.
While sulfonyl malonamide derivatives are known as herbicides (see patent reference 10), all of them are unsubstituted sulfonyl malonamide derivatives, and no reference is made to an AT2 receptor agonist for a sulfonyl malonamide derivative having a substituent at 2-position of the malonamide structure.
The AT2 receptor agonists reported up to current times have not been confirmed regarding the selectivity to other target molecules, pharmacokinetic property and/or safety. In addition, none of compounds successfully available or under development as a pharmaceutical product has been disclosed based on the mechanism of agonist action at AT2 receptor.    non-patent reference 1: Pharmacol. Rev., 52, 415-472 (2000)    non-patent reference 2: J. Med. Chem., 47, 5995-6008 (2004)    non-patent reference 3: J. Med. Chem., 49, 7160-7168 (2006)    patent reference 1: WO02/096883    patent reference 2: WO06/109058    patent reference 3: WO03/064414    patent reference 4: WO04/046128    patent reference 5: WO04/046137    patent reference 6: WO04/085420    patent reference 7: WO06/109056    patent reference 8: WO06/109058    patent reference 9: WO04/046141    patent reference 10: Indian patent No. 178290